Drugs to Recognize Exam I (August 15)

Question 1

Carbamazepine

Answer 1

3A4 inducer
induces 2C9 and 2C19

-induces enzyme responsible for its own metabolism, reducing levels of active drug over time

Prodrug (Prodrugs are inactive compounds that are metabolized in the body to their active forms)

Question 2

Rifampin

Answer 2

induce 3A4
induce 2C9 and 2C19

induces P-gp/MDR1 transporters (gut kidney liver efflux) increase drug efflux and decrease drug plasma conc

Question 3

Phenytoin

Answer 3

induce 3A4
zero-order kinetics of eliminations

restrictive hepatic clearance/low hepatic extraction (Q greater than f x CLint)

Little “first pass metabolism” when given orally. A change in binding or drug metabolism/excretion activity will have a greater effect on hepatic clearance than changes in liver blood flow. Capacity-limited clearance.

Question 4

Phenobarbital

Answer 4

induce 3A4

induce 2C9 and 2C19

Question 5

St. John’s wort

Answer 5

induces 3A4

induces P-gp/MDR1 transporters (gut kidney liver efflux) increase drug efflux and decrease drug plasma conc

Question 6

grapefruit juice

will bioavailability or half life be affected?

Answer 6

inhibits 3A4 in enterocytes (intestinal)
not hepatic 3A4

affects bioavailability NOT half life

Question 7

Clarithromycin

Answer 7

strong inhibitor of 3A4

3A4 catalyzes both hydroxylation and N-demethylation of Clarithromycin

Question 8

Ritonavir

Answer 8

strong 3A4 inhibitor
anti-HIV protease inhibitor
significant GI adverse effects limit its critical use; low dose has no GI effects but potently inhibits 3A4

Question 9

chemicals in cigarette smoke, charboiled food, cruciferous vegetables

Answer 9

induce 1A2 3 fold

smokers sometimes need higher doses of certain drugs metabolized by CYP1A2

Question 10

A patient presents with severe broken leg and is in extreme pain; you prescribe x amount of codeine but thirty minutes later is still writhing in pain; you double check the dose and that it was administered but there were no errors. What might explain this?

Answer 10

drug isn’t working
-codeine is a Prodrug

-patient has variant allele of 2D6 - could lead to poor metabolize and consequently decreased efficacy and lack of sedative effect

Question 11

N-acetyl benzoquinoneimine

Answer 11

this is a highly reactive metabolite generated from acetaminophen when phase II enzymes are saturated; usually is conjugated by glutathione; if glutathione is depleted then hepatotoxicity ensues

Question 12

sulfonamides

Answer 12

Sulfonamides may compete for protein binding and increase the unbound fraction of other drugs.

adding sulfonamide will increase distribution of other drug

Question 13

Warfarin

Answer 13

zero order kinetics of elimination

restrictive hepatic clearance/low hepatic extraction (Q greater than f x CLint)

Little “first pass metabolism” when given orally. A change in binding or drug metabolism/excretion activity will have a greater effect on hepatic clearance than changes in liver blood flow. Capacity-limited clearance.

patients with 2C9*2 or *3 have decreased metabolic inactivation of S warfarin (most potent form); increased conc. of active warfarin with standard dose; prone to experiencing bleeding events; patients require lower warfarin dosing

Question 14

lidocaine

Answer 14

exhibits NON-RESTRICTIVE HEPATIC CLEARANCE (Q is less than f x CLint)

Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance. Flow-dependent clearance: conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.

Question 15

propranolol

Answer 15

exhibits NON-RESTRICTIVE HEPATIC CLEARANCE (Q is less than f x CLint)

Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance. Flow-dependent clearance: conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.

Question 16

morphine

Answer 16

Phase II reactions will activate drug

(exceptions bc for most drugs Phase II inactivates)

ex of a parental drug that contains –OH, -COOH or –NH2 functional groups and can directly undergo Phase II metabolism without prior phase I metabolism

Question 17

minoxidil

Answer 17

Phase II reactions will activate drug

exceptions bc for most drugs Phase II inactivates

Question 18

Isoniazid

Answer 18

ex of a parental drug that contains –OH, -COOH or –NH2 functional groups and can directly undergo Phase II metabolism without prior phase I metabolism

Question 19

Irinotecan

Answer 19

Prodrug

Question 20

Codeine

Answer 20

Prodrug

Question 21

Prednisone

Answer 21

Prodrug

Question 22

Glucocorticoids

Answer 22

induce 3A4

Question 23

Fluconazole
Ketoconazole
Itranaconazole

Answer 23

inhibits 3A4

Question 24

Ritonavir

Answer 24

inhibits 3A4

Question 25

Erthyromycin

Answer 25

inhibits 3A4

Question 26

Cyclosporin

Answer 26

3A4 substrate (immunosuppressant drug to prevent organ rejection) potent inhibitor of OATP1B1 and blocks statin uptake INHIBITS P-gp/MDR1 transporters in gut kidney and liver (decreased drug elimination and increased drug plasma conc)

Question 27

elderly

Answer 27

decreased renal function decreased activity of Phase I metabolism

Question 28

chloramphenicol

Answer 28

given to babies (who have conjugating enzyme deficiency) will lead to build up of chloramphenicol oxidation metabolite which will result in gray baby syndrome and circulatory collapse and cyanosis

Question 29

pregnancy

Answer 29

some enzymes (2C9 2D6 and 3A4 increase) with others decrease (1A2, C219)

Question 30

alcohol

Answer 30

induces expression of 2E1

Question 31

pollutants and xenobiotics

Answer 31

induce specific p450 enzymes

Question 32

Disease

Answer 32

effect liver or blood flow to liver (cardiac disease)

Question 33

inflammatory cytokines

Answer 33

decrease expression of many CYP450 isoforms

Question 34

Probenecid

Answer 34

potent inhibitor of OAT1 Probenecid prevents Nephrotoxicity by blocking OAT1-dependent Cidefovir uptake into the proximal tubules great for preventing renal toxcitiy w Cidefovir… but now all OAT1 transporters inhibited… (can have effects on other drugs that utilize OAT1 elsewhere)

Question 35

Cidefovir

Answer 35

- anti-viral used to treat CMV retinitis - transported into proximal tubules by OAT1 - treatment limited by severe renal toxicity - Cidefovir always co-administered with probenecid bc it blocks uptake into the renal epithelium - will still be cleared eventually but this time through Glomerular filtration not through transport across renal epithelium

Question 36

Statins

Answer 36

OATP1B1 transport (BCRP efflux) SNP in OATP1BI influence STATIN efficacy and systemic exposure OATP1B1*5 and *15 have decreased transporter activity; decreased STATIN uptake and efficacy; increased systemic statin exposure and increased statin toxicity (*15 most commonly reduced in Caucasians, Asians, then African Americans) (Cyclosporin is potent inhibitor of OATP1B1 and blocks statin uptake) Statin in muscle causes myopathy and rhabdomyolysis

Question 37

metformin

Answer 37

very basic anti-diabetic drug that acts in the liver and is eliminated unchanged by renal tubular excretion (OCT/MATE SNPs result in loss of transporter activity and decreased kidney uptake/excretion so increased systemic drug availability)

Question 38

cimetidine

Answer 38

histamine H2 receptor antagonist used to treat acid peptic disorder (eliminated extensively via kidney) mediates lots of OCT/MATE interactions prevents renal elimination of other OCT dependent drugs -administered w Cisplatin and prevents Cisplatin-induced nephrotoxicity (non-selective inhibitor of several p450 isoforms)

Question 39

Cisplatin

Answer 39

chemotherapeutic agent to treat certain cancers -use limited by nephrotoxicity Co-administration of CIMETIDINE blocks Cisplatin uptake into the kidney and prevents Cisplatin-induced nephrotoxicity (primarily eliminated via renal tubular excretion)

Question 40

BBB

Answer 40

- tight junctions prevent ions and large molecules passing between endothelial cells - ABC transporters expressed on endothelial cells of BBB (P-gp/MDR1 BCRP MRP family efflux pumps) - prevent access of xenobiotic compounds (drugs) to the CNS - will exclude most drugs other than those small (less than 400Da and lipophilic)

Question 41

P-gp1/MDR1 (cancer connection)

Answer 41

- tumor cells often “upregulate” expression of P-gp/MDR1 - increased expression of P-gp/MDR1 in tumor cells is associated with a more aggressive phenotype, poorer prognosis and decreased sensitivity to chemotherapeutic drugs - increased expression of P-gp/MDR1 in tumor cells promotes efflux of anti-cancer drugs

Question 42

Through what transporter will glutathione, glucuronide and sulfate conjugates be excreted?

Answer 42

MRP

Question 43

Loperamide

Answer 43

opiod receptor agonist used to treat diarrhea substrate for P-gp and does not cross BBB Co administration w cyclosporin (P-gp inhibitor) allows Loperamide to cross BBB and can cause respiratory depression

Question 44

CYP2D6, 2C9 and 2C19

Answer 44

polymorphic together they metabolize approx 50% of the 200 most commonly used drugs - significant variation in enzyme activity between individuals - polymorphisms are clinically significant (2D6) Significant polymorphisms and levels of enzyme activity between ethnic groups

Question 45

2C19*1 2C19*2 and *3 2C19*17

Answer 45

* 1 normal * 2 and *3 non functional * 17 increased expression/increased activity

Question 46

2C9*2 and *3 | 2C9*15 and *25

Answer 46

* 2 and *3 reduced function variants * 15 and *25 null variants 2C9*2 or *3 have decreased metabolic inactivation of S warfarin (most potent form); increased conc. of active warfarin with standard dose; prone to experiencing bleeding events; patients require lower warfarin dosing

Question 47

VKORC1

Answer 47

direct target of warfarin common polymorphism is 1639 G to A G is associated with higher VKORC1 expression and a higher warfarin dose A is associated with lower VKORC1 expression and a lower warfarin dose needed (90% Asians carry A allele, 37% whites, 14% Africans) Rare mutations in the VKORC1 coding region are associated with warfarin resistance (reduced affinity) that require v. high doses of warfarin to achieve anticoagulation

Question 48

OATP1B1*15

Answer 48

polymorphisms in drug transporters causing elevated drug levels OATP1B1*15 results in increased statins and increased risk of myopathy

Question 49

HLA-B*1502

Answer 49

Carbamazepine-induced Steven Johnson Syndrome in Han Chinese FDA recommends Pharmacogenetic testing to be used to screen Asian patients requiring carbamazepine in order to avoid SJS Drug-induced hypersensitivity reactions (Allergic-like reactions, often life threatening)

Question 50

Trastuzumab (Herceptin)

Answer 50

an anti-Her2/ErbB2 monoclonal antibody used to treat breast cancer in patients whose tumor overexpresses the Her2/ErbB2 receptor

Question 51

Imatinib (Gleevac)

Answer 51

a tyrosine kinase inhibitor specific for the BCR-ABL Chr breakpoint oncoprotein found in patients with Chronic Myeloid Leukemia

Question 52

Gefitnib (Iressa)

Answer 52

an EGFR tyrosine kinase inhibitor used to treat a subset (10-20%) of Non-Small cell lung cancers patients that harbor the L858R activating mutation in their EGFR

Question 53

Ritonavir

Answer 53

potent 3A4 inhibitor anti-HIV protease inhibitor -significant GI adverse effects limit its use clinically (low doses of Ritonavir has no GI effects but potentially inhibits 3A4 so will decrease first pass metabolism of Lopinavir "boosting" its levels -enhanced anti-HIV effect

Question 54

Ethanol/chronic alcohol

Answer 54

induce p450 enzymes - chronic alcohol induces expression of CYP2E1 can result in N-acetyl benzoquinoneimine metabolite from acetaminophen higher first pass metabolism in men than women

Question 55

What is tachyphylaxis?

Answer 55

rapid development of tolerance to drug's effects describes the rapid development of diminished responsiveness to a drug.